Cells of the neuroendocrine system secrete neuropeptide hormones that modulate a diverse array of physiological activities. In addition to neurotransmission, neuropeptides regulate secretory functions of adenohypophysial and pancreatic cells as well as cells of the adrenal cortex and the digestive system. The hormone termed neuropeptide Y is co-released with norepinephrine from postganglionic neurons and participates along with that hormone in regulating vascular smooth muscle tone and maintaining blood pressure. Agonists and antagonists of neuropeptide-Y are therefor useful in treating clinical disorders relating to both hypotension and hypertension.
Receptor binding ligands are typically polypeptides, for example, neuropeptide-Y, a 36 amino acid polypeptide sequence whose composition is known. Receptor activity can be inhibited by competitive binding of an antagonist of the neuropeptide to the Y-receptor. Several synthetic antagonist species of neuropeptide-Y have been developed. Among these are corresponding amino acid sequences wherein some of the native L-amino acids are replaced by corresponding D-amino acids (U.S. Pat. No. 5,328,899).
Neurons bind neuropeptide-Y through several distinct Y-receptors; receptors Y1, Y2, Y3, Y4, Y5 are known. The neuroendocrine Y1 receptor is one of those believed to be particularly associated with appetite, and synthetic neuropeptide ligands that selectively bind to the Y1 receptor and have antagonistic activity to neuropeptide-Y are believed to be anorectic agents useful in treating obesity.
Other non-peptide neuropeptide-Y antagonist species have been developed for pharmacologic use. Among these are benzylamine derivatives of molecular systems comprising phenyl, thienyl, pyridyl or pyrimidine groups (Peterson, J M et al. WO9614307); sulfanilyl derivatives of quinoline (Downing, D M et al. 211th Amer. Chem. Soc. Meeting, March 1996); phenylsulfonyl derivatives of aniline-based compounds (Wright, J L et al., 211 Amer. Chem. Soc. Meeting, March, 1996); raloxiphene, and a benzothiophene derivative of pyrrolidine or piperidino groups having antiestrogen properties (U.S. Pat. No. 5,504,094 to Bruns et al.). Also described are sulfamyl derivatives of phenylalanine-amidine-containing compounds (U.S. Pat. No. 5,506,258 to Christophe et al.); and bicyclic neuropeptide-Y receptor antagonists comprising substituted benzofurans, benzothiophenes, or indoles (WO96/12489 to Eli Lilly).